Notch3-dependent ß-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC.

ABSTRACT

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of ß-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which ß-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of ß-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call "adaptive persisters". We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with ß-catenin, leading to increased stability and activation of ß-catenin. We demonstrate that the combination of EGFR-TKI and a ß-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and ß-catenin inhibition in patients with EGFR mutant lung cancer.